Psychedelics W I T H D A LT O N Gisel Murillo [ C O M P A N Y V I S I O N ] "To make the impossible possible. Dalton Pharma Services uses its scientific and pharmaceutical expertise to bring customer ideas to life. We develop their new drug products, optimize the synthesis of therapeutic candidates, and manufacture them at the highest level of quality." [ S E R V I C E S ] Contract Research Custom Synthesis Medicinal and Flow Chemistry API Process Development Formulation Development cGMP API Manufacturing cGMP Sterile Filling Analytical and Microbiology Services FDA inspected, HC approved, & MRA with EMA What are Psychedelics? Psychedelics Psychedelics are a subset of hallucinogenic drugs that alter mood, cognitive processes, and consciousness by influencing how neurotransmitters operate at the synapses of the central nervous system. The consumption of certain psychedelics may produce unpleasant, frightening, or pleasant visual and auditory hallucinations. [1] Some of the most well-known psychedelic drugs include LSD, peyote, psilocybin, and DMT. Psychedelics are controlled substances around various regulatory agencies due to their high potential for abuse. However, research has shown that psychedelics may play a role in treatments for psychiatric disorders. [1] Psilocybin is currently undergoing clinical studies for its potential to treat various conditions such as anxiety, depression, obsessive-compulsive disorder, and problematic drug use. However, there are currently no approved therapeutic products containing psilocybin in Canada or the US. [2, 3] Did You Know? [4, 5] Mental illness can cut 10 to 20 years from a person’s life 10-20 years expectancy Mental illness affects people of all ages, education, income levels, and cultures 264 million Depression affects 264 million people worldwide Mental health will indirectly affect all Canadians, and 1 in 5 people in Canada will personally experience a mental health problem 284 million Anxiety affects 284 million people worldwide The current and ongoing financial impacts of COVID- 19 have negatively impacted people's mental health 75% of children with mental health problems do not have 75% access to specialized treatment services Types of Psychedelics Psychedelic hallucinogens are classified by their primary mode of action. Classical Psychedelics [6, 7] Classical psychedlics exert their effects primarily by an agonist (or partial agonist) action on brain serotonin 5-hydroxytryptamine (5-HT) 2A receptors. [8] Classical psychedelics include: LSD Mescaline (Lysergic acid diethylamide) (3,4,5- trimethoxyphenylathylamine) Found in a fungus that grows Found in small spineless on rye and other grains cactus, mescaline is the active Hallucinogenic, synthetic ingredient in peyote substance, can cause bad trips Psilocybin DMT [3-(2-Dimethylaminoethyl)-1H-indol- (N, N-dimethyltryptamine) 4-yl] dihydrogen phosphate Hallucinogenic chemical Naturally occurring psychedelic compound found in many plants prodrug found in "magic and animals mushrooms," hallucinogenic, can cause bad trips Other Psychedelics [6, 7] A few other drugs that produce psychedelic effects but have a different mechanism of action are entactogens and dissociative or psychedelic anesthetics. Entactogens – exert their effects primarily by an antagonist action on the N-methyl- D-aspartate (NMDA) subtype of the glutamate receptor. [1, 9] Entactogens include: 3,4-Methyl enedioxy methamphetamine or MDMA Also known as “ecstasy” or “molly,” addictive, harmful short-and-long-term mental and physical effects Dissociative or psychedelic anesthetics include: Ketamine Causes detachment from reality, may lead to risk-taking behaviours, sometimes used as a “date rape” drug, surgery anesthetic for humans and animals PCP Phencyclidine Also known as “angel dust,” causes detachment from reality, may lead to risk- taking behviours, surgery anesthetic no longer used due to serious side effects * bad trips = non-ordinary states of consciousness MAeBcOhUaT nism of Action Mechanism of Action Overview Psychedelics are agonists or partial agonists at brain serotonin receptors, meaning they activate serotonin upon binding. Psychedelics predominantly target 5-hydroxytryptamine 2A (5-HT2A receptors). 5-HT2A is an excitatory postsynaptic receptor and a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin. Psychedelics particularly target 5-HT2A expressed on apical dendrites of neocortical pyramidal cells in layer V. [1] This triggers a dramatic increase in the release of the excitatory neurotransmitter glutamate in the cortical, thalamic, and limbic regions. [10] [11] Mechanism of Action for LSD, Psilocybin, and DMT [12] LSD is a semi-synthetic tryptamine. LSD acts primarily upon 5-HT2A and 5-HT1A receptors, and partly upon the dopamine (DA) receptors D1 and D2 and the adrenergic α2 receptors. This causes an increase in cortisol, oxytocin, and adrenaline levels. Psilocybin is dephosphorylated by hepatic first- pass metabolism. Psilocybin acts primarily upon 5- HT2A, 5-HT1A, and 5-HT2C receptors. DMT acts primarily upon 5-HT2A, 5-HT2C, 5-HT1A receptors, sigma-1, and trace amine-associated receptors (TAARs). The sigma-1 agonist is responsible for immunomodulatory and anti- inflammatory properties, whereas TAARs are mediators of consciousness and perception. Legislation/Regulation Controlled substances have a higher-than-average potential for abuse or addiction. Therefore, their improper use can result in harm to public health or safety. That is why these drugs and their substances are regulated. Controlled substances and drugs are categorized into schedules. Psychedelics are one of the many drug classes classified as controlled substances. These controlled substances require specialized licensing, or a granted exemption from the governing authority to be handled legally. Canada All legislative documents related to controlled substances are contained in the Controlled Drugs and Substances Act, the Narcotic Control Regulations, Parts G and J of the Food and Drug Regulations, and the Benzodiazepines and Other Targeted Substances Regulations. The Controlled Drugs and Substance Act sets out ten schedules (2 repealed) for controlled substances including LSD, peyote, psilocybin, DMT, and MDMA. Part G and J of the Food and Drug Regulations require authorization from Health Canada for controlled substances, such as psychedelics, to be regulated for possession, production, sale, transportation, and import and export for clinical trials or research purposes. J.01.001 Restricted drug means (a) any substance that is set out in the schedule to Part J or anything that contains the substance (b) cocaine (benzoylmethylecgonine) or any of its salts J.01.004 (1) The following persons are authorized to have a restricted drug in their possession: (a) a licensed dealer (b) a qualified investigator who possesses the drug for the purpose of conducting clinical testing or laboratory research in an institution (c) an inspector, member of the Royal Canadian Mounted Police, police constable, peace officer, member of the technical or scientific staff of the Government of Canada, the government of a province or a university in Canada who possesses the drug in connection with their employment (d) a person exempted under section 56 of the Act with respect to the possession of that drug (e) the Minister Most psychedelics are categorized as Schedule 3 controlled substances. Schedule 3 includes LSD and psilocybin. MDMA and ketamine are listed under Schedule 1. Failure to comply with laws may lead to punishments such as: Issuance of warning letters Requirement of corrective action plans Suspending and revoking licences, permits, or exemptions Imprisonment Fines Legislation/Regulation USA Legislative documents related to controlled substances are contained in the FDA sections 811 to 814 and in the FDA regulations Title 21, Chapter II, Part 1308. 812. (a) contains the five schedules of controlled substances. The schedules established in this section are updated annually. Schedule I High potential for abuse No currently accepted medical use in treatment in the United States Lack of accepted safety Schedule II High potential for abuse There is accepted medical use in treatment in the United States Abuse may lead to severe psychological or physical dependence Schedule III Potential for abuse less than schedules I and II drugs There is currently accepted medical use in treatment in the United States Abuse may lead to moderate or low physical dependence or high psychological dependence Schedule IV Low potential for abuse There is currently accepted medical use in treatment in the United States Abuse may lead to limited physical dependence or psychological dependence Schedule V Low potential for abuse There is currently accepted medical use in treatment in the United States Abuse may lead to limited physical dependence or psychological dependence 812. (c) sets out the list of controlled substances under Schedules I, II, III, IV, and V including LSD, peyote, psilocybin, DMT, and MDMA. 821 to 832. Describes registration of manufacturers, distributors, and dispensers of controlled substances. Every person who manufactures, distributes, or dispenses a controlled substance, requires a registration issued by the Attorney General unless exempted by section 956 or under 1301.22 through 1301.26 of regulations. Each controlled substance has been assigned an “Administration Controlled Substances Code Number” Registration requirements are highlighted in section 823 Labelling